Combined PD-1, BRAF and MEK inhibition in BRAF V600E colorectal cancer: a phase 2 trial.
Jun TianJonathan H ChenSherry X ChaoKarin PelkaMarios GiannakisJulian M HessKelly P BurkeVjola JorgjiPrincy SindurakarJonathan BravermanArnav MehtaTomonori OkaMei HuangDavid LiebMaxwell SpurrellJill N AllenThomas A AbramsJeffrey W ClarkAndrea C EnzingerPeter C EnzingerSamuel J KlempnerNadine Jackson McClearyJeffrey A MeyerhardtDavid P RyanMatthew B YurgelunKatie N KanterEmily E Van SeventerIslam BaievGary ChiJoy JarnaginWilliam B BradfordEdmond WongAlexa G MichelIsobel J FetterGiulia SiravegnaAngelo J GemmaArlene H SharpeShadhmer DemehriRebecca LearyCatarina D CampbellOmer YilmazGad A GetzAparna Raj ParikhNir HacohenRyan B CorcoranPublished in: Nature medicine (2023)
While BRAF inhibitor combinations with EGFR and/or MEK inhibitors have improved clinical efficacy in BRAF V600E colorectal cancer (CRC), response rates remain low and lack durability. Preclinical data suggest that BRAF/MAPK pathway inhibition may augment the tumor immune response. We performed a proof-of-concept single-arm phase 2 clinical trial of combined PD-1, BRAF and MEK inhibition with sparatlizumab (PDR001), dabrafenib and trametinib in 37 patients with BRAF V600E CRC. The primary end point was overall response rate, and the secondary end points were progression-free survival, disease control rate, duration of response and overall survival. The study met its primary end point with a confirmed response rate (24.3% in all patients; 25% in microsatellite stable patients) and durability that were favorable relative to historical controls of BRAF-targeted combinations alone. Single-cell RNA sequencing of 23 paired pretreatment and day 15 on-treatment tumor biopsies revealed greater induction of tumor cell-intrinsic immune programs and more complete MAPK inhibition in patients with better clinical outcome. Immune program induction in matched patient-derived organoids correlated with the degree of MAPK inhibition. These data suggest a potential tumor cell-intrinsic mechanism of cooperativity between MAPK inhibition and immune response, warranting further clinical evaluation of optimized targeted and immune combinations in CRC. ClinicalTrials.gov registration: NCT03668431.
Keyphrases
- single cell
- metastatic colorectal cancer
- immune response
- pi k akt
- wild type
- signaling pathway
- free survival
- end stage renal disease
- clinical trial
- rna seq
- ejection fraction
- newly diagnosed
- oxidative stress
- prognostic factors
- randomized controlled trial
- cancer therapy
- machine learning
- patient reported outcomes
- big data
- inflammatory response
- toll like receptor
- open label
- quality improvement
- mesenchymal stem cells
- study protocol
- human health
- artificial intelligence
- placebo controlled
- phase iii
- double blind
- cone beam